Abstract

OBJECTIVE—It has been shown that adults with either long-standing type 1 or type 2 diabetes had lower skeletal muscle strength than
nondiabetic adults in cross-sectional studies. The aim of the study was to investigate longitudinal changes of muscle mass
and strength in community-dwelling older adults with and without type 2 diabetes.

RESEARCH DESIGN AND METHODS—We examined leg and arm muscle mass and strength at baseline and 3 years later in 1,840 older adults aged 70–79 years in
the Health, Aging, and Body Composition Study. Regional muscle mass was measured by dual energy X-ray absorptiometry, and
muscle strength was measured using isokinetic and isometric dynamometers.

In industrialized countries, the major increase in the number of people with diabetes is attributed to the aging of the population
(1,2). In older adults, diabetes is associated with a two- to threefold increased risk of injurious falls (3) and physical disability (4–8). Several factors have been identified as contributors to diabetes-related disability including obesity (4,5), coronary heart disease (4,5,7), stroke (4), arthritis (4,5), depression (7), and visual impairments (4,5), but still a large portion of the diabetes-disability relationship is not explained by these factors. Alterations in muscular
function in diabetes, which can be a potential pathway, have not yet been explored.

Muscle weakness in diabetes has been considered a rare manifestation associated with severe diabetic neuropathy (9). However, recent studies using quantitative assessments of muscular function showed that skeletal muscle strength, especially
in the lower extremity, is generally lower in adults with diabetes than in nondiabetic subjects (10–12). The Health, Aging, and Body Composition Study (Health ABC) was designed to investigate the impact of changes in body composition
and health conditions on age-related physiological and functional status among adults from 70 to 79 years of age. In this
cohort, we have reported that older adults with type 2 diabetes had lower skeletal muscle strength and quality (12). However, it is still unclear whether lower muscle strength in diabetes is a consequence of diabetes or just a coincidence
because previous studies were cross-sectional observations. To address this question, we reexamined knee extensor and hand
grip strength and body composition 3 years after the initial examination in the Health ABC Study. We hypothesized that older
adults with type 2 diabetes would show a greater decline in skeletal muscle strength and quality than older adults without
diabetes.

RESEARCH DESIGN AND METHODS—

The Health ABC Study included well-functioning, community-dwelling older adults aged 70–79 years. The Health ABC Study was
described in detail elsewhere (12). Among 2,618 participants who had completed baseline assessments for skeletal muscle mass and strength, 1,840 (70.3%) were
reexamined 3 years later. The reasons for not having follow-up data were death (n = 146), development of disability and/or institutionalization (n = 302), missed contact (n = 77), withdrawal of the participants (n = 11), inability to perform a knee strength test (n = 191), and missing data on body composition (n = 51). All participants provided informed consent before participating in the study. The consent forms and study protocols
were approved by the institutional review boards at each field center.

Diabetes assessment

Participants were considered to have type 2 diabetes if they had 1) a report of having the diagnosis of diabetes with onset after age 25 and/or 2) current use of oral hypoglycemic medications or insulin, or 3) a fasting plasma glucose concentration ≥7.0 mmol/l at baseline. Plasma glucose was measured using an automated glucose oxidase
reaction (Vitros 950 analyzer; Johnson & Johnson, Rochester, NY), and A1C was measured by an enzymatic method (Bio-Rad, Hercules,
CA).

Body composition

Lean masses of the upper and lower extremities and the total body were assessed using dual-energy X-ray absorptiometry (QDR
4500, software version 8.21; Hologic, Bedford, MA). The validity and reproducibility of the body composition data in the Health
ABC Study may be found elsewhere (13,14). Quality assurance measures included the use of a body composition phantom for calibration and annual assessment for potential
site differences or drift over time.

Strength assessments

Strength was measured using an isokinetic dynamometer (125 AP; Kin-Com, Chattanooga, TN) for knee extension and isometric
dynamometer (Jaymar; JLW Instruments, Chicago, IL) for hand grip strength. For knee extension, maximal voluntary concentric
isokinetic torque was assessed in Newton meters at an angular velocity of 60°/s. At least three, but no more than six, maximal
efforts were allowed to produce three overlying curves, and the mean maximal torque was recorded and used for the analysis.
The right leg was used unless contraindicated by pain or history of joint replacement. For validation of the knee strength
assessments, we performed a reliability study in 63 participants. The interexaminer coefficient of variation (CV) was 4.85%
with no significant differences between examiners. The intraparticipant CV was 10.68%, and the CV for combined effect of examiner
and participant was 11.73%.

Isometric grip strength was assessed for each hand. Participants with severe hand pain or recent surgery were excluded. The
vast majority of participants (96%) who had leg strength testing also had grip strength testing. For these analyses, we used
the maximum of the force from two trials for the right upper extremity. A measure of muscle quality (leg-specific torque [Newton
meters per kilogram] and arm-specific force [kilograms per kilogram]) was created by taking the ratio of strength to the entire
corresponding leg or arm muscle mass in kilograms measured by dual-energy X-ray absorptiometry.

Other covariates

Sociodemographic characteristics included age, sex, race, and education. Combined chronic diseases such as coronary heart
disease, congestive heart failure, stroke, peripheral artery disease, knee osteoarthritis, depression, and cancer were identified
by self-report and confirmed by treatment and medication use. Self-reported poor eyesight was considered as impaired vision.
Renal insufficiency was defined by serum creatinine level >1.5 mg/dl in men and 1.2 mg/dl in women (15). The ankle-arm index was calculated, and subclinical peripheral artery disease was defined by ankle-arm index <0.9. Health-related
behaviors including smoking, alcohol drinking, and level of physical activity (kilocalories per week) were determined by using
a standardized questionnaire (16). Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured in duplicate using an ultrasensitive enzyme-linked
immunosorbent assay (R&D Systems, Minneapolis, MN). The lower limit of detection was <0.10 pg/ml for IL-6 and 0.18 pg/ml for
TNF-α, with CVs of 6.3 and 16.0%, respectively.

Statistical analyses

Baseline characteristics of the cohort are presented separately for those with and without diabetes. χ2 tests were calculated for categorical variables, and a Student's t test was used for continuous variables to test for any statistical differences between the two groups. Longitudinal changes
of muscle strength and quality were calculated in both absolute terms and relative terms (percent change from baseline). Differences
between older adults with and without diabetes were assessed by general linear models controlling for sex, race, age, and
clinic site (model 1). Additional adjustments were made for BMI, baseline strength or quality, changes in muscle mass, and
physical activity (model 2), plus combined chronic diseases and diabetes-related complications (model 3) and inflammatory
cytokines (log-transformed IL-6 and TNF-α in model 4). P < 0.05 was accepted as statistically significant. All of the analyses were performed using SPSS software (version 12.0.0;
SPSS, Chicago, IL).

RESULTS—

Among the 1,840 older adults with complete assessments of baseline and follow-up skeletal muscle mass and strength tests,
305 (16.6%) had type 2 diabetes at baseline. Older adults with type 2 diabetes were more likely to be men and black and to
have a lower level of education (Table 1). Those with diabetes had greater body weight, BMI, and total fat mass as well as higher total lean mass than their nondiabetic
counterparts. As expected, combined chronic conditions such as coronary heart disease, peripheral artery disease, impaired
vision, and renal insufficiency were more prevalent in those with type 2 diabetes. IL-6 and TNF-α levels were significantly
higher in older adults with diabetes (Table 1).

Both diabetic and nondiabetic older adults lost significant amounts of initial muscle strength in 3 years. However, older
adults with type 2 diabetes lost their knee extensor strength more rapidly than those without diabetes (P = 0.001) (Table 2). Older adults with type 2 diabetes also lost greater amounts of leg lean mass than those without diabetes (P < 0.05). Furthermore, muscle quality (maximal strength per unit of muscle mass in Newton meters per kilogram) declined more
rapidly in older adults with type 2 diabetes (P < 0.05). When expressed in relative changes, older adults with type 2 diabetes showed ∼50% more rapid declines in knee extensor
strength (−9.0 vs. −13.5%, P = 0.002) and muscle quality (−6.2 vs. −10.0%, P = 0.01) in 3 years than those without diabetes. However, the changes in hand grip strength and arm muscle quality were not
different between those with and without diabetes although older adults with diabetes lost greater amounts of arm muscle mass
(Table 2). There was no indication of an interaction effect (P < 0.10) of sex or race with diabetes on the changes in muscle strength or muscle quality.

A greater decline of leg muscle quality in older adults with type 2 diabetes was also evident, even after adjustments for
demographics, BMI, baseline muscle quality, changes in leg lean mass, and physical activity (P = 0.001, model 2). Further adjustments for combined chronic diseases and inflammatory cytokines attenuated the association
of diabetes and declines in muscle quality. However, the greater declines in muscle strength and quality in older adults with
type 2 diabetes remained significant throughout the adjustment models (Table 3).

CONCLUSIONS—

In this study, older adults with type 2 diabetes lost 13.5% of their knee extensor strength, whereas those without diabetes
lost 9.0% of initial strength in 3 years. An ∼50% more rapid decline in the knee extensor strength in older adults with diabetes
was not accounted for by a greater loss of leg muscle mass. Muscle quality also declined more rapidly in older adults with
type 2 diabetes, suggesting that diabetes may result in functional impairments in muscular function of the lower extremities,
not necessarily accompanied by loss of muscle mass.

Sarcopenia, a status of decreased skeletal muscle mass, is commonly observed in older adults as a result of age-related loss
of muscle mass (17–21). In general, it is frequently accompanied by lower skeletal muscle strength. However, determinants or risk factors for sarcopenia
and low muscle strength in older adults have not been well identified (22). This is the first epidemiological study showing that type 2 diabetes is associated with rapid loss of skeletal muscle mass
and strength in older adults. It confirms the previous cross-sectional finding of lower muscle strength in individuals with
diabetes (10–12). It is also consistent with the finding of Andreassen et al. (23) who showed a rapid decline in ankle strength in patients with symptomatic diabetic neuropathy. The findings of this longitudinal
study strongly suggest that low muscle strength in adults with type 2 diabetes is a consequence of rather than just a coincidence
with type 2 diabetes.

We found discordance between the upper and lower extremities for diabetes and changes in muscle strength. A relative preservation
of upper extremity strength has been observed in the process of aging (21,24). Our findings are, in fact, consistent with previous cross-sectional studies showing decreased skeletal muscle strength
at the ankle and knee but not at the wrist and elbow in patients with type 2 diabetes (10). Andersen et al. (11) reported that upper extremity strength was preserved even in long-standing type 1 diabetic patients. They also found that
muscle strength was related to the presence and severity of peripheral neuropathy in both type 1 and type 2 diabetic patients
(10,11). It is well known that the lower extremities are predominantly involved in diabetic neuropathy presumably because of a length-dependent
degeneration of nerve fibers (25,26). If neuropathy is a factor, skeletal muscle function is more likely to be affected in the lower extremities than in the
upper extremities.

The exclusion of many participants for follow-up knee extensor strength test may have potentially biased the results to the
null because proportionally more subjects with diabetes were excluded because of high mortality and other reasons (see Table 1 of the online appendix, available at http://dx.doi.org/10.2337/dc06-2537). We identified 47 participants with diabetes and 181 without diabetes who were excluded from the knee strength test but
had the grip strength test at the follow-up examination. Among them, declines in hand grip strength were greater in older
adults with diabetes than in those without diabetes (−3.3 ± 6.7 vs. −1.1 ± 6.2 kg, P < 0.05), suggesting that strict criteria for knee strength testing might select stronger individuals and actually obscure
the true declines in muscle strength, particularly in those with diabetes (see Table 2 of the online appendix).

Lower extremity strength is essential for maintaining basic physical function, especially mobility such as walking and climbing
stairs. It is well known that lower knee extensor strength is associated with an increased risk of incident mobility limitations
(27–29). Although it is unclear whether there is a certain threshold level of leg strength to maintain physical function, lower
muscle strength is definitely a risk factor for physical disability, independent of lower muscle mass itself (29).

Several studies suggested that the combination of sarcopenia and obesity (“sarcopenic obesity”) was more strongly associated
with disability than either body composition type alone (30,31). It is possible that the rapid decline in muscle strength in older adults with type 2 diabetes may be associated with sarcopenic
obesity. However, to our knowledge there is no study examining the changes in muscle strength in relation to sarcopenic obesity.

The mechanisms for the rapid loss of skeletal muscle strength, in older adults with diabetes are not known. Neuropathic processes
involving motor neurons could affect muscle strength, as evidenced by the close association of muscle strength and severity
of diabetic neuropathy in the previous cross-sectional observations (10,11). Electrophysiological studies showed that muscle strength in diabetic patients correlated with fiber density and amplitude
of the macromotor unit potential, suggesting incomplete reinnervation after axonal loss (32). Longitudinal studies suggest an average loss of compound muscle action potential amplitude at a rate of ∼3%/year in patients
with type 2 diabetes over a 10-year period (33). Further research should identify the role of the decrease in motor amplitudes on skeletal muscle strength and quality in
subjects with diabetes.

In our study, adjustments for comorbid conditions such as cardiovascular disease, stroke, congestive heart failure, peripheral
arterial disease, depression, impaired vision, and renal insufficiency slightly attenuated the declines in muscle strength.
These results suggest that chronic complications of diabetes have a limited role in declines in skeletal muscle strength in
older adults with diabetes. However, we had no reliable assessment of nerve function in our study at baseline. It is possible
that declines in muscle function may indeed be the result of diabetic neuropathy (23).

Another potential mechanism is increased levels of inflammatory cytokines in subjects with diabetes. It has been reported
that systemic inflammatory cytokines such as TNF-α and IL-6 have detrimental effects on muscle mass, strength, and physical
performance in older adults (34,35). In our study, rapid declines in muscle strength and quality in older adults with diabetes are attenuated, albeit still
significant, after adjusting for IL-6 and TNF-α. These findings may suggest a potential role of inflammatory cytokines on
the muscular function in diabetes.

Our study has several limitations. The study participants were well-functioning, community-dwelling older adults who were
relatively healthier than other individuals in the typical population of the same age. There were many dropouts, and only
∼70% of participants completed follow-up assessments. However, we believe that the loss to follow-up may produce an underestimation
of the true decline in muscle function in those with diabetes (see Tables 1 and 2 of the online appendix). The questionnaire to assess physical activity in the Health ABC Study has not been validated in
older diabetic subjects. It may not be sensitive enough to detect the influence of different physical activity level on the
changes in muscle strength and quality in our study. We also lacked information about neuropathy at baseline, which would
be related with muscular function in those with type 2 diabetes.

In summary, the present study demonstrates an accelerated loss of knee extensor strength and quality in older adults with
type 2 diabetes.

Acknowledgments

This study was supported by National Institute on Aging Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and in part
by the Intramural Research program of the National Institutes of Health, National Institute on Aging. Parts of this study
were presented orally at the 65th annual meeting of the American Diabetes Association, San Diego, California, 10–14 June 2005.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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